Aging, Oxidative Stress and Cell Death

衰老、氧化应激和细胞死亡

• 批准号: 7569451
• 负责人: BRIAN A. HERMAN
• 金额: $ 106.93万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569451
• 关键词: Aging; Oxidative; Stress; Cell; Death

DESCRIPTION (provided by applicant): Study of the role of oxidative stress in the etiology of aging has represented a multi-departmental and multidisciplinary area of research at UTHSCSA for over twenty years. This collaborative effort has resulted in significant research breakthroughs and successful applications for external funding by the participating investigators. Studies funded by this and other current and previous program project grants have led to the development of a number of transgenic/knockout mouse models animal models that coupled with new and novel optical imaging approaches developed in the last funding cycle, were used to test the hypothesis that oxidative stress contributes to aging by altering mitochondrial structure and function. Over the first five years of this program project, 38 publications (~8/year), 4 in press, 7 submitted and 13 in preparation manuscripts and abstracts have resulted from the collaborative work of this group. There were a number of major findings during the previous funding cycle including the establishment of a direct correlation between oxidant stress induced mitochondrial-dependent apoptosis and aging, a demonstration that loss of mitochondrial DMA is associated with a compensatory increase in mitochondrial mass and an increase in lysosomal mass putatively to remove damaged mitochondria, the discovery that while astrocytic neuronal protection decreases during aging, it is possible to enhance astrocytic neuronal protection in an aged animal through a mitochondrial dependent pathway, and most remarkably and unexpectedly of all, that genetically reducing various antioxidant enzymes in the mitochondria did not negatively impact the lifespan of these animals; in fact, a reduction in glutathione peroxidase 4 expression resulted in a significant increase in longevity. Collectively these findings have led us to reassess the importance of mitochondrial oxidative stress per se as the sole regulator of the aging process, and instead to focus on the contributions of age-dependent response to mitochondrial stress (i.e. mitochondrial function, autophagy and apoptosis) in aging. During the next funding period, our objectives are to identify novel mechanisms responsible for mitochondrial contributions to the aging phenotype including mechanisms responsible for caspase-2 medicated apoptosis in the development of age-related osteoporosis, how aging impacts the cellular response to the stress of mito DNA depletion, whether modulation of the mitochondrial dependent-apoptotic pathway can delay aging and extend lifespan, and whether upregulation of mitochondrial-dependent metabolism can be neuroprotective during aging. We believe that these studies should have practical consequences in the identification of molecular targets for rational new drug discovery in this field.

描述（由申请人提供）：二十多年来，氧化应激在衰老病因学中的作用研究代表了 UTHSCSA 的多部门和多学科研究领域。这项合作努力取得了重大研究突破，并成功申请了参与研究人员的外部资金。由本项目以及其他当前和之前的项目资助资助的研究已导致开发了许多转基因/基因敲除小鼠模型动物模型，这些动物模型与上一个资助周期开发的新的和新颖的光学成像方法相结合，用于检验假设氧化应激通过改变线粒体结构和功能而导致衰老。在该计划项目的前五年中，共发表 38 篇出版物（约 8 篇/年），其中 4 篇已出版，7 篇已提交，13 篇正在准备手稿 和摘要是该小组协作工作的结果。在上一个资助周期中有许多重大发现，包括建立氧化应激诱导的线粒体依赖性细胞凋亡与衰老之间的直接相关性，证明线粒体 DMA 的损失与线粒体质量的补偿性增加和线粒体质量的增加有关。溶酶体质量被认为可以去除受损的线粒体，这一发现表明，虽然星形胶质细胞神经元保护在衰老过程中降低，但有可能通过线粒体依赖性途径增强老年动物的星形胶质细胞神经元保护，并且最显着的是出乎意料的是，从基因上减少线粒体中的各种抗氧化酶并没有对这些动物的寿命产生负面影响；事实上，谷胱甘肽过氧化物酶 4 表达的减少会导致寿命显着延长。总的来说，这些发现使我们重新评估线粒体氧化应激本身作为衰老过程唯一调节因子的重要性，并重点关注年龄依赖性反应对线粒体应激（即线粒体功能、自噬和细胞凋亡）的贡献。老化。在下一个资助期内，我们的目标是确定线粒体对衰老表型贡献的新机制，包括在与年龄相关的骨质疏松症发展中负责 caspase-2 药物凋亡的机制，衰老如何影响细胞对线粒体应激的反应DNA耗竭、线粒体依赖性细胞凋亡途径的调节是否可以延缓衰老和延长寿命，以及线粒体依赖性代谢的上调是否可以在衰老过程中起到神经保护作用。我们相信，这些研究应该在该领域合理新药发现的分子靶标识别方面产生实际影响。